Increased sensitivity to cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells in response to treatment with 12-O-tetradecanoylphorbol 13-acetate.
The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) enhanced sensitivity to cis-diamminedichloroplatinum(II) (DPP) in human ovarina carcinoma 2008 cells by a factor of 2.53 +/- 0.74 fold (S.D.). Sensitization was maximum 3 h after a 1-h exposure to TPA and had disappeared completely by 7 h after treatment. An equivalent degree of sensitization was produced in a 2008 variant selected for 10-fold resistance to DDP. TPA neither increased nor decreased cellular accumulation of DDP. Phorbol, a TPA analog which does not activate protein kinase C, did not cause sensitization. This synergistic interaction between TPA and DDP was completely inhibited by pretreatment with staurosporine, a protein kinase C inhibitor. Cellular cAMP was not altered by TPA stimulation. Furthermore, cycloheximide, a potent protein synthesis inhibitor, did not block the TPA-induced enhancement of drug sensitivity. These results strongly suggest that DDP sensitivity can be modulated by protein kinase C and regulated by phosphorylation of a protein kinase C substrate in both intrinsically sensitive and DDP-resistant cells.
Isonishi
S
S
Department of Medicine, University of California, San Diego, La Jolla 92093.
Andrews
P A
PA
Howell
S B
SB
D000470:Alkaloids / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000470:Alkaloids; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin